Six-Month Dienogest Therapy Reduced the Endometrioma Size, Pelvic Pain, And CA-125 Levels

Endometriosis; Dienogest; Endometrioma; Pelvic pain; CA-125 8

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Endometriosis affects approximately 10% of women of reproductive age and is 10 associated with pelvic pain, infertility, and reduced quality of life. Dienogest is widely used for 11 medical management. This study evaluated the effects of dienogest on endometrioma size, serum 12 CA-125 levels, and pelvic pain. 13

In this retrospective study, medical records of 45 women aged 18 –49 years who 14 received oral dienogest (2 mg/day) for at least six months were reviewed. Endometrioma size was 15 assessed by ultrasound, pelvic pain using the Visual Analog Scale (VAS), and serum CA -125 16 levels from laboratory records. Baseline and six-month values were compared using the Wilcoxon 17 test and correlations were analyzed using Spearman’s test. 18

After six months of treatment, significant reductions were observed in endometrioma size 19 and V AS scores (p<0.001) and CA-125 levels (p0.05). A significant negative correlation was identified between patient age 22 and post-treatment endometrioma size (r = −0.320, p<0.05). 23

Six months of dienogest therapy was associated with significant improvements in 24 lesion size, pain, and biochemical markers. Dienogest may represent an effective medical 25 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2 treatment option for symptomatic patients, particularly for those seeking to avoid surgery and 26 preserve ovarian reserve. 27

28 Endometriosis is a chronic, estrogen -dependent inflammatory disease characterized by the 29 presence of endometrial -like tissue outside the uterine cavity and affects approximately 10% of 30 women of reproductive age (Zondervan et al., 2018; Zondervan et al., 2020). It is a major cause of 31 dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility, significantly impairing quality of 32 life and work productivity (Zondervan et al., 2020; Giudice & Kao, 2004). Ovarian endometriomas 33 are among the most common manifestations of the disease and are frequently associated with 34 pelvic pain, infertility, and reduced ovarian reserve (ESHRE Guideline, 2022; Dunselman et al., 35 2014). 36 Management of endometriosis should be individualized based on symptom severity, disease 37 extent, age, and reproductive plans. Although surgery may be effective in selected cases, repeated 38 surgical interventions may lead to adhesions and decreased ovarian reserve (Dunselman et al., 39 2014; ACOG, 2010). Therefore, long -term medical therapy aimed at symptom control and 40 suppression of disease activity has become a cornerstone of management, particularly in patients 41 who wish to preserve fertility. 42 Dienogest, a fourth-generation oral progestin, exerts antiproliferative, anti-inflammatory, and anti-43 angiogenic effects on endometriotic lesions (Foster & Wilde, 1998; McCormack, 2010). Previous 44 studies have demonstrated its effectiveness in reducing endometriosis-related pain and improving 45 patient-reported outcomes (Andres et al., 2015; Römer, 2018; Sağlık Gökmen et al., 2023). In 46 addition to symptomatic improvement, suppression of lesion activity may result in reductions in 47 endometrioma size and serum CA -125 levels, which may reflect disease activity in moderate to 48 severe cases. 49 Although several studies have reported the clinical benefits of dienogest, real -world data 50 simultaneously evaluating its effects on endometrioma size, pelvic pain severity, and CA -125 51 levels remain limited. Assessment of these parameters together may provide a more 52 comprehensive evaluation of treatment response in routine clinical practice. Therefore, the aim of 53 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 3 this study was to investigate the effects of six months of dienogest therapy on endometrioma size, 54 pelvic pain assessed by the Visual Analog Scale (VAS), and serum CA-125 levels in patients with 55 endometriosis. 56

57 Study design and setting 58 This retrospective study was conducted in the Department of Obstetrics and Gynecology at a 59 tertiary care training and research hospital in Istanbul, Turkey. Medical records of patients 60 followed in the endometriosis and chronic pelvic pain outpatient clinic were reviewed. Clinical 61 data at presentation were compared with findings obtained after treatment. 62 Study population 63 Patients aged 18 –49 years with a diagnosis of endometriosis who had received regular oral 64 dienogest therapy (2 mg/day) for at least six months were eligible for inclusion. A total of 45 65 patients who met the predefined inclusion and exclusion criteria were included in the final analysis. 66 Patients were excluded if they were younger than 18 or older than 49 years, had known or 67 suspected breast cancer, a history of venous thromboembolism, active smoking status, a history of 68 malignancy, known liver disease, or diabetes mellitus with cardiovascular complications. Clinical 69 and laboratory data were retrospectively obtained from the hospital information system (HIS) and 70 outpatient clinic records. 71 Ultrasound assessment 72 Endometrioma measurements were performed using transvaginal ultrasonography with a 5 -MHz 73 probe (Esaote). In virgin patients, transabdominal ultrasonography was used. All measurements 74 were performed by two experienced gynecologists with more than 10 years of experience in the 75 endometriosis unit. The largest diameter (mm) of the dominant endometrioma was recorded and 76 used for analysis. 77 78 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 4 79 Outcome measures 80 Pelvic pain assessment: Pelvic pain severity was evaluated using the Visual Analog Scale (VAS), 81 ranging from 0 (no pain) to 10 (worst imaginable pain). VAS scores recorded at baseline and after 82 at least six months of treatment were compared. 83 84 85 86 87 88 89 90 Figure 1: Visual analog scale with numeric pain rating scale used in this study. Pain intensity was 91 assessed using a 0 –10 numeric rating, where 0 indicates no pain, and 10 indicates the worst imaginable 92 pain. Participants were asked to select the number that best represented their perceived pain level at the 93 time of assessment. This figure has been copied from Gift A.G., 1989. 94 Serum CA-125: Serum CA-125 levels were obtained from hospital laboratory records at baseline 95 and after treatment. Changes in CA -125 levels were used to assess the biochemical response to 96 therapy. 97 Endometrioma size: Endometrioma size was evaluated using ultrasonography before treatment 98 and after at least six months of therapy. The maximum diameter of the largest endometrioma was 99 recorded in millimeters. 100 Statistical analysis 101 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 5 Descriptive statistics for continuous variables were presented as mean ± standard deviation, 102 median, minimum, and maximum values, while categorical variables were expressed as number s 103 and percentages. Normality of continuous data was assessed using the Shapiro–Wilk test. 104 Comparisons between baseline and six -month values for VAS score, CA -125 level, and 105 endometrioma size were performed using the Wilcoxon signed -rank test. Z values represent the 106 test statistics of the Wilcoxon analysis. V AS scores range from 0 (no pain) to 10 (worst imaginable 107 pain). Endometrioma size is expressed in millimeters (mm) and CA -125 levels in units per 108 milliliter (U/mL). A p-value < 0.05 was considered statistically significant. 109 Correlations between endometrioma size, VAS score, and CA -125 levels were analyzed using 110 Spearman’s correlation coefficient. Spearman’s correlation coefficients (r) were calculated to 111 assess the relationship between endometrioma size and V AS scores and serum CA -125 levels at 112 baseline and post-treatment. A p-value < 0.05 was considered statistically. In addition, as indicated 113 above, Spearman’s rank correlation analysis was performed to assess the association between 114 patient age and clinical parameters at baseline and after six months of treatment. Correlation 115 coefficients (r) and corresponding p -values are presented. A p -value < 0.05 was considered 116 statistically significant. 117 Statistical analyses were performed using IBM SPSS for Windows version 20.0 (SPSS Inc., 118 Chicago, IL, USA). A p-value <0.05 was considered statistically significant. 119 120

121 In this study, 45 patients with endometrioma were evaluated. The mean age of the patients was 35 122 years (range: 23–47 years). Chronic comorbidities were present in 4.4% of patients (n = 2). Among 123 these, one patient had asthma, and the other had hyperprolactinemia. Medication use was reported 124 in 4.4% of patients (n = 2); one patient was using an inhaler , and the other was receiving 125 cabergoline (Dostinex). No personal or family history of malignancy was identified in the study 126 population. Baseline demographic and clinical characteristics are presented in Table 1, where age 127 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 6 is expressed as mean ± standard deviation and median (range), and chronic disease and medication 128 use are reported as numbers (n) and percentages (%) (Table 1). 129 130 Table 1. Baseline characteristics of the study population. 131 Variable Mean Value Age (years) 34.78 ± 7.61 Median (range) 34 (23–47) Chronic disease, n (%) n % No 43 95.6 Yes 2 4.4 Medication use, n (%) No 43 95.6) Yes 2 4.4 132 Table 2. Comparison of VAS scores, CA -125 levels, and endometrioma size at baseline and at six 133 months of treatment. 134 Before treatment Baseline Post Treatment 6 Months Mean ± SD Median (Min-Max) Mean ± SD Median (Min-Max) Test statistics p VAS 6.69±2.25 7 (0-10) 3.64±2.55 3 (0-10) Z=-4.881 <0.001 d CA-125 (U/mL:) 61.85±58.25 41 (8-363) 39.02±29.95 31 (8-146) Z=-3.058 0.002 d Endometrioma size (mm) 50.22±22.77 45 (18-118) 38.24±20.43 35 (16-118) Z=-4.216 <0.001 b d: Wilcoxon test 135 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 7 We observed a significant reduction in pelvic pain, serum CA-125 levels, and endometrioma size 136 after six months of dienogest therapy (Table 2). After six months of dienogest therapy, significant 137 decreases were observed in all evaluated clinical and radiological parameters (Table 2). A 138 significant difference was observed between baseline and six-month V AS scores (p < 0.001). V AS 139 scores at six months were significantly lower compared to pretreatment values (Table 2). Serum 140 CA-125 levels were also significantly reduced following six months of dienogest treatment. A 141 significant difference was observed between baseline and six -month CA-125 levels (p < 0.01) 142 (Table 2). Similarly, endometrioma size showed substantial reduction after treatment. The median 143 lesion size decreased from 45 mm to 35 mm. Endometrioma size at six months was significantly 144 smaller compared to pretreatment measurements (Table 2). 145 We then evaluated the relationship between endometrioma size and clinical parameters to 146 determine whether lesion size was associated with pain severity or serum CA -125 levels. No 147 significant correlation was found between baseline endometrioma size and baseline V AS scores (p 148 > 0.05). Similarly, no significant correlation was observed between baseline endometrioma size 149 and baseline CA-125 levels (p > 0.05) (Table 3). Likewise, no significant correlation was identified 150 between post -treatment endometrioma size and post -treatment V AS scores (p > 0.05). No 151 significant association was observed between post -treatment endometrioma size and post -152 treatment CA-125 levels (p > 0.05) (Table 3). 153 Table 3. Correlation between endometrioma size and clinical parameters at baseline and after six 154 months of treatment. 155 Endometrioma size before treatment r* p Pre-treatment VAS 0.010 0.949 Post-treatment CA-125 0.152 0.319 Endometrioma size after treatment r* p Pre-treatment VAS 0.283 0.073 Post-treatment CA-125 0.216 0.175 *Spearman’ s Correlation Coefficient 156 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 8 Afterwards, we examined whether patient age was associated with baseline and post -treatment 157 clinical parameters. No significant correlation was found between patient age and baseline 158 endometrioma size, VAS scores, or CA -125 levels (p>0.05). Similarly, no significant correlation 159 was observed between patient age and post -treatment VAS scores or CA -125 levels (p>0.05). 160 However, a significant negative correlation was identified between patient age and post-treatment 161 endometrioma size (r = −0.320, p<0.05), indicating that endometrioma size decreased with 162 increasing age. 163 Table 4: Correlation between patient age and baseline and post-treatment endometrioma size, VAS 164 scores, and CA-125 levels. 165 Age r* p Baseline VAS -0.072 0.638 Baseline CA-125 0.008 0.959 Baseline Endometrioma Size -0.143 0.347 Post-treatment VAS -0.147 0.336 Post-treatment CA-125 -0.249 0.099 Post-treatment Endometrioma Size -0.320 0.041 *Spearman’ s Correlation Coefficient 166

167 In this study, six months of treatment with 2 mg/day oral dienogest in 45 patients with 168 endometrioma resulted in significant reductions in endometrioma size, pelvic pain severity (VAS 169 score), and serum CA-125 levels. However, no correlation was observed between endometrioma 170 size and VAS score or CA -125 levels. These findings suggest that while dienogest effectively 171 reduces disease activity and symptom burden, lesion size alone may not directly reflect symptom 172 severity or biochemical markers. 173 Symptom control remains the primary goal in the management of endometriosis (Ferrero et al., 174 2018). Current guidelines from the American Society for Reproductive Medicine recommend 175 medical therapy as the first -line approach for patients with superficial or persistent disease, 176 reserving surgical treatment for those with large endometriomas or disease refractory to medical 177 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 9 management (ASRM, 2014). Effective medical therapies that reduce symptoms and suppress 178 lesion activity are therefore essential, particularly for patients who wish to avoid surgery and 179 preserve ovarian reserve. 180 Previous studies have not clearly demonstrated superiority between estrogen –progestin 181 combinations and progestin -only therapies in terms of efficacy, safety, tolerability, or cost 182 (Vercellini et al., 2016). Some patients using combined oral contraceptives may experience pain 183 during hormone-free intervals due to withdrawal bleeding; in such cases, continuous rather than 184 cyclic use is recommended (Zorbas et al., 2015; Vercellini et al., 2018). Because endometriosis is 185 a chronic disease requiring long-term treatment, progestins may be preferred as first -line therapy 186 in patients who cannot tolerate or have contraindications to combined oral contraceptives 187 (Vercellini et al., 2016). 188 Dienogest is a selective progestin that suppresses local estrogen production and inhibits the 189 proliferation of endometrial cells. It also partially suppresses hypothalamic GnRH secretion, 190 leading to decreased LH and FSH levels and reduced ovarian estrogen production. These 191 mechanisms create a hypoestrogenic environment that limits the growth and activity of ectopic 192 endometrial tissue. Dienogest has no androgenic, glucocorticoid, or mineralocorticoid activity and 193 is characterized by high oral bioavailability and a pharmacokinetic profile suitable for once -daily 194 administration (McCormack et al., 2010). 195 The effectiveness of dienogest in reducing endometriosis -associated pain has been demonstrated 196 in several clinical studies. Römer et al. (2018) reported significant long-term reductions in pelvic 197 pain scores in women receiving 2 mg/day dienogest, both after surgery and as primary treatment. 198 Similarly, Sağlık Gökmen et al. (2023) evaluated 64 patients treated with dienogest and reported 199 significant reductions in both endometrioma size and pain scores. In our study, mean 200 endometrioma size decreased from 50.2 mm to 38.2 mm, and the mean VAS score decreased from 201 6.69 to 3.64, supporting the lesion-suppressive and symptom-relieving effects of therapy. 202 Chen et al. (2024) also demonstrated significant reductions in pain scores, endometrioma size, and 203 CA-125 levels after six months of dienogest treatment. In their study, endometrioma size decreased 204 by approximately 35% after six months, and CA -125 levels showed marked improvement. Our 205 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 10 findings of reduced CA-125 levels and decreased lesion size are consistent with these observations. 206 These effects may be attributed to dienogest-induced stromal atrophy within endometriotic lesions, 207 decreased cellular proliferation, and a consequent reduction in active ectopic endometrial tissue. 208 Furthermore, as endometriosis is associated with peritoneal irritation and inflammation, the anti -209 inflammatory effects of dienogest may contribute to the observed decline in serum CA-125 levels. 210 The strength of the present study is the simultaneous evaluation of clinical, radiological, and 211 biochemical treatment outcomes in a real -world clinical setting. Assessing endometrioma size, 212 pain severity, and CA-125 levels together provides a more comprehensive assessment of treatment 213 response. 214 However, several limitations should be acknowledged. The retrospective design, relatively small 215 sample size, and absence of a control group limit the generalizability of the findings. In addition, 216 the follow -up period was limited to six months, and long -term outcomes were not evaluated. 217 Larger prospective studies with longer follow-up are needed to confirm these results. 218 Overall, our findings suggest that dienogest is an effective medical treatment option for patients 219 with endometriosis, providing significant improvements in symptoms and disease -related 220 parameters while potentially reducing the need for surgical intervention. 221 222

223 In this study, six months of dienogest therapy was associated with significant reductions in 224 endometrioma size, pelvic pain severity, and serum CA-125 levels. These findings support the use 225 of dienogest as an effective and well-tolerated treatment option that may delay the need for surgical 226 intervention, particularly in patients who wish to preserve fertility. 227

OF STUDY 228 The relatively small sample size, retrospective design, and short follow -up period limit the 229 generalizability of these findings. Future prospective, randomized studies with larger patient 230 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 11 populations and longer follow -up are needed to confirm the long -term efficacy and safety of 231 dienogest therapy. 232

233 1) Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med . 234 2020;382(13):1244–1256. 235 2) Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. 236 Endometriosis. Nat Rev Dis Primers. 2018;4:9. 237 3) Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799. 238 4) European Society of Human Reproduction and Embryology (ESHRE). ESHRE guideline: 239 Endometriosis. 2022. 240 5) Dunselman GAJ, Vermeulen N, Becker C, et al. ESHRE guideline: management of women 241 with endometriosis. Hum Reprod. 2014;29(3):400–412. 242 6) American College of Obstetricians and Gynecologists (ACOG). Management of 243 endometriosis. ACOG Practice Bulletin No. 114. Obstet Gynecol. 2010;116(1):223–236. 244 7) American Society for Reproductive Medicine (ASRM). Treatment of pelvic pain 245 associated with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927–935. 246 8) Foster RH, Wilde MI. Dienogest. Drugs. 1998;56(5):825–833. 247 9) McCormack PL. Dienogest: a review of its use in the treatment of endometriosis. Drugs. 248 2010;70(16):2073–2088. 249 10) Andres MP, Borrelli GM, Abrão MS. Dienogest in the treatment of endometriosis: 250 systematic review. Arch Gynecol Obstet. 2015;292(3):523–529. 251 11) Römer T. Long -term treatment of endometriosis with dienogest: a real -world 252 study. Gynecol Endocrinol. 2018;34(6):513–516. 253 12) Sağlık Gökmen N, et al. Effects of dienogest treatment on endometrioma size and pain 254 symptoms. J Obstet Gynaecol Res. 2023;49(3 255 13) Chen X, et al. Clinical outcomes of dienogest treatment in women with endometriosis: a 256 retrospective study. Eur J Obstet Gynecol Reprod Biol. 2024 257 14) Vercellini P, et al. Medical treatment of endometriosis-related pain. Hum Reprod Update. 258 2016;22(3):314–335. 259 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 12 15) Vercellini P, et al. Continuous use of oral contraceptives for endometriosis -associated 260 pain. Fertil Steril. 2018;109(3) 261 16) Zorbas KA, et al. Continuous versus cyclic oral contraceptives in endometriosis. Gynecol 262 Endocrinol. 2015;31(6):473–476. 263 17) Luciano DE, et al. Management of endometriosis: individualized treatment strategies. Clin 264 Obstet Gynecol. 2011;54(4):485–496. 265 18) Gift, A. G. (1989). Visual analogue scales: Measurement of subjective 266 phenomena. Nursing Research, 38(5), 286–288. 267 FIGURES/TABLES 268 Table 1. Baseline characteristics of the study population (n = 45). 269 Table 2. Comparison of V AS scores, CA-125 levels, and endometrioma size at baseline and at six 270 months of treatment. 271 Table 3. Correlation between endometrioma size and clinical parameters at baseline and after six 272 months of treatment. 273 Table 4: Correlation between patient age and baseline and post-treatment endometrioma size, 274 VAS scores, and CA-125 levels. 275 ACKNOWLEDGMENTS 276 We would like to thank the staff of the Endometriosis and Chronic Pelvic Pain Clinic at Bagcılar 277 Training and Research Hospital for their support in patient follow-up and data management. 278 FUNDING 279 The authors received no specific funding. 280 CONFLICT OF INTEREST 281 The authors declare no competing interests. 282 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint 13 ETHICS/IRB STATEMENT 283 The study was approved by the Clinical Research Ethics Committee of the University of Health 284 Sciences Ba gcılar Training and Research Hospital. Due to the retrospective design, informed 285 consent was waived. 286 DATA AVAILABILITY STATEMENT 287 Data are available from the corresponding author upon reasonable request. 288 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted March 24, 2026. ; https://doi.org/10.64898/2026.03.20.26348926doi: medRxiv preprint